Showing papers in "British Journal of Clinical Pharmacology in 1976"

A review of the animal pharmacology of labetalol, a combined alpha- and beta-adrenoceptor-blocking drug.

Abstract: 1 The animal pharmacology of labetalol, a drug that blocks both alpha- and beta-adrenoreceptors, is reviewed. 2 In isolated tissues the blockade by labetalol of both alpha- and beta-adrenoreceptors satisfied accepted critera for competitive antagonism. In contrast phentolamine was a competitive antagonist at alpha-adrenoreceptors only, and propranolol a competitive antagonist at beta-adrenoreceptors only. Labetalol was 6-10 times less potent than phentolamine in blocking alpha-adrenoreceptors and 1.5-3 times less potent than propranolol in blocking beta-adrenoreceptors. Labetalol itself was 4-8 times more potent at beta- than at alpha-adrenoreceptors. 3 In anaesthetized dogs labetalol given intravenously blocked vasopressor responses to phenylephrine positive chronotropic, vasodepressor and bronchodilator response to isoprenaline. Phentolamine blocked the effect of phenylephrine only, and propranolol the effects of isoprenaline only. Labetalol was about 7 times less potent than phentolamine in blocking alpha-adrenoreceptors, about 4 times less potent than propranolol in blocking cardiac beta1-adrenoreceptors, and 11-17 times less potent than propranolol in blocking vascular and bronchial beta2-adrenoceptors. This difference in the relative potency of labetalol arises because propranolol is a slightly more potent antagonist at beta2- than at beta1-adrenoreceptors. Labetaol itself was about 16 times more potent at cardiac beta1- than at vascular alpha-adrenoreceptors. In conscious dogs labetaol given orally blocked vasopressor responses to phenylephrine and positive chonotropic responses to isoprenaline. 4 In anesthetized dogs and pithed rats labetaol blocked alpha- or beta-adrenoreceptor-mediated responses to sympathetic nerve stimulation and intravenously administered phenylephrine or isoprenaline to approximately the same extent. 5 Labetalol does not possess partial agonist (intrinsic sympathomimetic) activity at cardiac beta1-adrenoreceptors. 6 The blocking action of labetalol both in vivo was shown to be specific for alpha- and beta-adrenoreceptors. 7 The haemodynamic effects of labetalol are attributable to its adrenoreceptor-blocking actions. The observed responses vary from one experiment situation to another depending on the balance of autonomic influences. For example, in barbitone-anaesthetized dogs, in which sympathetic tone predominates, both labetalol and propranolol reduced heart rate, contractility, output and work--effects which are attributable to beta-adrenoreceptor blockade. Labetalol differed from propranolol in decreasing rather than increasing total peripheral resistance and in causing larger falls in blood pressure at equipotent beta-adrenoreceptor-blocking doses. These differences are probably attributable to peripheral vasodilatation resulting from the vascular alpha-adrenoreceptor-blocking action of labetalol...

Factors affecting drug binding in plasma of elderly patients.

Abstract: The binding of salicylate, sulphadiazine and phenylbutazone to plasma proteins has been studied in young and elderly subjects. Elderly patients had significantly reduced concentrations of plasma albumin, compared with subjects under 40 years of age. Sifnificant increases in free levels of all three drugs were found in elderly patients receiving multiple drug therapy, and a correlation obtained with the number of drugs being taken. It is suggested that because of their low albumin levels, elderly patients may be more susceptible to the effects of multiple drug therapy on drug binding. The clinical implications of these observations are discussed.

Metabolism of labetalol by animals and man

Abstract: 1 The disposition and metabolism of labetalol and either 14C- or 3H-labetalol has been studied in mouse, rat, rabbit, dog and man. 2 Radiolabelled labetalol was administered orally at doses of 100 mg/kg to the mouse, up to 50 mg/kg to the rat and rabbit, 20 mg/kg to the dog and 200 mg to man. From measurements of the total plasma radioactivity it was shown that labetalol was well absorbed by all the species. When the measurements of plasma radioactivity and labetalol concentrations were compared, it was found labetaol had been extensively metabolized by the first-pass effect in rat, rabbit and man. Metabolism by this route occurred to a lesser extent in the dog. 3 Radiochemical analysis of the tissues from rats, rabbits and dogs showed that the highest concentrations of radioactivity were found in the lung, liver and kidney. Very little radioactivity was present in the brain. Over 99% of the radioactivity was cleared from the tissues by 7 d. When doses of up to 200 mg 14C-labetalol/kg were given to pregnant rats and 50 mg 14C-labetalol/kg to pregnant rabbits, autoradiographic and radiochemical analysis of the full-term foetuses showed that only small amounts of radioactivity were present in the foetus. 4 The mouse excreted 72%, the rate 48%, the rabbit 61%, the dog 66% and man 60% of the oral dose of radioactivity in the urine. Analysis of themouse and rat faeces showed that the remainder of the dose of radioactivity was excreted in the faeces. 5 Radiochemical analysis of the urine and faeces collected from rats and dogs after an intravenous dose of 1 mg 14C- and 3H-labetalol/kg showed that excretion of radioactivity occurred via both the kidney and bile. 6 An intravenous dose of 1 mg 3H-labetalol/kg to dog and 1 mg 'cold' labetalol/kg to man was not as extensively metabolized as a similar oral dose. 7 The percentage of the dose excreted in the urine as unchanged drug was 2% in the rabbit, 11% in the rat, 19% in the dog and up to 5% in man. The O-phenyl glucuronide was the major metabolite present in the mouse, rat, and rabbit urine. Dog and man also formed this metabolite, but to a lesser extent. A second glucuronide was the major metabolite present in dog urine. This was probably formed through conjugation of glucuronic acid was the secondary alcohol group of labetalol. The major metabolite present in human urine was an unidentified conjugate of labetalol. Minor metabolites of labetalol present in rat, rabbit and dog urine were hydroxylabetalol and its glucuronyl conjugate.

Assessment of alpha- and beta-adrenoceptor blocking actions of labetalol.

Abstract: Isoprenaline dose-response curves plotting increases in heart rate before and after labetalol are suggestive of competitive antagonism at beta-adrenoceptor sites. Phenylephrine dose-response curves using increases in systolic pressure before and after labetalol are suggestive of competitive antagonism at alpha-adrenoceptor sites. The ratio of alpha:beta-adrenoceptor antagonism induced by labetalol is approximately 1:3. Peak pharmacological responses after a single oral dose of labetalol (400 mg) occurred between 90-120 min after administration.

Distribution and removal of human serum albumin‐technetium 99m instilled intranasally.

Abstract: The efficacy of antiviral drugs and vaccines administered intranasally may depend upon the technique of application. The distribution and time-course of removal of human serum albumin-technetium 99m (HSA-Tc 99m)-instilled intranasally were studied in eleven healthy volunteers using a gamma camera and an anterior sodium iodide scintillation detector. In 100 randomized studies material was delivered as drops in the supine position or as a spray to seated subjects. A significantly higher proportion of 'good' distributions (62 in 73 tests) was obtained with drops compared with spray (1 in 27). The volume administered was varied between 0.10 ml and 0.75 ml and the concentration of HSA was changed from 3 to 30% with no significant effect upon the distribution of time-course of removal; pertechnetate in isotonic saline was distributed and removed in a manner comparable to HSA-Tc 99m. Activity recorded by the detector showed an initial rapid fall associated with removal of most of the material from the nasal cavity, followed by a slower decline associated with the removal of material mainly from the anterior region of the nose. A multidose study confirmed that frequent administration by drops is required to maintain a high level of activity in the nasal cavity. Using this technique it should be possible to correlate measurements of antiviral efficacy and vaccines take-rates with certain characteristics of intranasal applicators; such studies may lead to the design of better devices.

Human pharmacokinetic and pharmacodynamic studies on the atenolo (ICI 66,082), a new cardioselective beta-adrenoceptor blocking drug.

Abstract: The beta-adrenoceptor blocking effects of orally administered atenolol on tachycardia induced by intravenous isoprenaline or by exercise have been studied in normal volunteers, and compared with the effects of similar doses of propranolol. The blood levels of atenolol at various times after oral administration were determined by g.l.c. and correlated with the degree of inhibition of tachycardia. Atenolol was shown to be a beta-adrenoceptor blocker in man, as in animals, in that it antagonized the chronotropic effects of isoprenaline and of exercise. The inhibitory effect of atenolol on exercise-induced tachycardia was evident at a concentration in blood of 0.2 mug/ml and virtually complete at 0.5 mug/ml. Higher concentrations than this did not produce significantly greater blockade. The effects of atenolol on exercise-induced tachycardia were similar to those of propranolol but it was less effective in blocking the rise in heart rate and fall in diastolic blood-pressure induced by intravenous infusion of isoprenaline. This separation of effects is considered characteristic of drugs causing preferential blockade of cardiac beta-adrenoreceptors. The half-life of atenolol in blood was calculated to ablut 9 hours.

A study of factors influencing drug disposition in chronic liver disease, using the model drug (+)-propranolol.

Abstract: The pharmacokinetics, following i.v. administration of (+)-propranolol (40 mg) have been compared to in vitro measurement of protein binding and biochemical parameters of liver function in six normal subjects and twenty patients with stable chronic liver disease. The clearance of (+)-propranolol decreased with evidence of increasing severity of impairment of liver function correlating significantly with a fall in serum albumin, a rise in bilirubin and a prolongation in prothrombin index. The clearance of (+)-propranolol correlated with and was numerically similar to the clearance of indocyanine green in normal subjects and also in patients with chronic liver disease. Protein binding was decreased in chronic liver disease, but this change was not related to changes in plasma proteins. In normal subjects and patients without ascites the volume of distribution increased with decreases in protein binding. Ascites was associated with a further increase in the volume of distribution. The considerable variation in half-life largely depends on changes in liver blood flow, the degree of protein binding and the plasma protein pool size.

The effect of metoprolol and practolol on lung function and blood pressure in hypertensive asthmatics

Abstract: The effect of metoprolol, a new beta1-adrenoceptor blocking agent, was compared to practolol in the treatment of hypertension in seventeen asthmatics during concurrent optimum bronchodilator therapy with a selective beta2-adrenoceptor-stimulant. The two beta-adrenoceptor antagonists were given at two dose levels, practolol (200 mg and 400 mg) daily, and metoprolol (100 mg and 200 mg) daily, in a twice-daily dosage schedule, at 12 h intervals, for 17 days. The comparison was made double-blind and a crossover design was used. The drugs were given in randomized order. The study started with a run-in placebo period and there was a washout period on placebo between the treatment periods. Spirometry, blood pressures and heart rates were recorded in a standardized manner. At the lower dose levels no influence on FEV1 was noted, and no difference was found between the two active drugs. At the higher dose level FEV1 was reduced by both beta-adrenoceptor-blocking drugs. Four out of twelve patients given the higher dose experienced exacerbation of their asthma. The heart rate fell with both drugs and at both dose levels. During the placebo period a marked increase of heart rate was noted. The blood pressure fell at both dose levels compared to placebo, no difference being recorded between the two drugs. Metoprolol and practolol are equally effective beta1-adrenoceptor blocking drugs. In this study it was found that metoprolol could be used in asthmatics who had indications for beta-adrenoceptor blockade, provided that the total daily dose did not exceed 100 mg. Optimal bronchodilator treatment with a bronchoselective beta-adrenoceptor agonist is an absolute prerequisite in order to avoid the risk of aggravation of asthma.

Residual effects and skills related to driving after a single oral administration of diazepam, medazepam or lorazepam.

Abstract: Psychomotor skills and visual functions related to driving were measured double-blind cross-over in ten healthy volunteers before, and 1,3,5 and 7 h after a single oral administration of diazepam (10mg), medazepam (15 mg) or lorazepam (2.5 mg). The late effects of lorazepam were tested in seven other subjects 12 and 24 h after the administration. Lorazepam impaired almost all the measured skills more (P less than 0.05 to 0.001) than diazepam, medizepam or the placebo. The lorazepam impairment of reactive skills and flicker fusion discrimination remained statistically significant (P less than 0.05) for as long as 12 h. Medazepam impaired only reactive skills and flicker fusion, the latter remaining impaired (P less than 0.05) for as long a 5 h after the administration. The magnitude and duration of the effects of diazepam were intermediate between those of lorazepam and medazepam. Diazepam impaired perceptual speed and reactive and co-ordinative skills as well as flicker fusion discrimination and visual parameters related to driving. Slight impairments in performance were measurable for up to 5 h after administration but at 7 h the results resembled those measured after the placebo. The lack of alterations in adaptation to darkness, sensitivity to brightness or visual discrimination ability in bright counterlight at a time when flicker fusion discrimination was severely depressed suggests that an impaired ability to discriminate flickering light is of no or little clinical significance to driving ability. It is concluded that patients receiving a 2.5 mg dose of lorazepam should not drive or operate machinery for 24 h after the administration. After diazepam (10 mg) or medazepam (15 mg) patients should refrain from driving or participating inskilled performances for only 5 to 7 hours.

Pharmacological effects of labetalol in man.

Abstract: 1 The pharmacological effects of labetalol have been studied in normal healthy subjects. The results of these studies are reviewed. 2 In the evaluation of the beta-adrenoreceptor-blocking effects of labetalol various indices of beta-adrenoceptor blockade in man were used. Labetalol administered orally and intravenously competitively antagonized the effects of isoprenaline on heart rate and diastolic blood pressure. The beta-adrenoceptor blockade induced was regarded as 'non-selective'. In addition, labetalol produced dose-related inhibitory effects on exercise-induced increases in heart rate any systolic blood pressure and similar dose-related inhibitory effects on the tachycardia induced by valsalva's manoeuvre. Labetalol had only a modest inhibitory effect on the tachycardia induced by tilting since blood pressure was reduced on a dose-related basis. 3 Labetalol was a specific competitive antagonist of the alpha-adrenoceptor agonist effects of systemically administered phenylephrine and locally infused noradrenaline. In addition, oral and intravenous administration of labetalol reduced systolic and diastolic blood pressure in the supine, standing and sitting positions. 4 The onset and duration of the alpha- and beta-antagonist effects of oral labetalol did not seem to be dissociated in time and there was a close correlation between the change in plasma concentration and pharmacological effects. 5 In comparative studies with propranolol, similar beta-antagonist effects were observed but propranolol was 4-6 times more potent weight for weight. Precise comparison, however, was complicated by the combined alpha- and beta -effects of labetalol, especially as the predominant effect of labetalol in normotensive subjects was to reduce blood pressure; whereas the predominant effect of propranolol was to reduce heart rate. In addition propranolol had inhibitory effects on ventilatory function in normal subjects, whereas labetalol in equivalent beta-adrenoreceptor-blocking doses did not. 6 From the details of the studies reviewed it was concluded that in man labetalol possesses combined alpha- and beta-adrenoreceptor antagonist properties.

The relationship between liver volume, antipyrine clearance and indocyanine green clearance before and after phenobarbitone administration in man.

Abstract: Liver volume and the clearances of antipyrine and indocyanine green have been measured before and after administration of phenobarbitone (180 mg/day) for 3 weeks to ten healthy subjects. The measurement of liver volume by an ultrasound scanning technique yielded reproducible results which were consistent with predictions of liver size by allometric methods. Before phenobarbitone, antipyrine clearance correlated with liver volume, but there was no correlation between indocyanine green clearance and liver volume. Phenobarbitone administration increased the clearance of antipyrine significantly by 90 +/- 14% but there was no significant change in indocyanine green clearance or liver volume. After phenobarbitone the correlation between antipyrine clearance and liver volume persisted. There was no correlation between indocyanine green clearance and liver volume. These results suggest that in non-medicated subjects some of the difference in antipyrine clearance is due to difference in functional hepatic parenchymal mass and that phenobarbitone increases the drug metabolising capacity per unit of hepatic mass but not total liver size.

Labetalol in long-term treatment of hypertension.

Abstract: 1 Labetalol, a beta- and alpha-adrenoreceptor-blocking drug, has been used in the treatment of hypertension in a total of 32 patients for over 4.5 yr, 14 patients for 3 yr or more. 2 Labetalol seems to have a similarly potency of methyldopa and the adrenergic neurone-blocking drugs. 3 Postural hypotension was only observed at doses over 2 g/d. It was the reason for stopping treatment in two patients. 4 Dosage varied; average 889 mg/d, range 75-3,200 mg. Tolerance did not develop. 5 Side-effects led to drug withdrawal in four patients

Digoxin pharmacokinetics: multicompartmental analysis and its clinical implications.

Abstract: The kinetics of digoxin have been investigated in healthy volunteers using an isotopic tracer technique. A three compartment open kinetic model has been proposed as the simplest model consistent with the plasma, urinary and faecal data obtained. The renal clearance of digoxin (mean +/- s.d.) was found to be 119+/-10 ml/min, which did not differ significantly from the glomerular filtration rate (110+/-14 ml/min). Digoxin extra-renal clearance (mean+/-s.d.) was found to be 47+/-7 ml/min. The model predicts that the tissue concentration attained after four 0.25 mg oral doses spread over 24 h can be achieved within a period of 4 h following a single oral loading dose of 1 mg. Maintenance doses can be derived from a simple formula based on the glomerular filtration rate, extra-renal clearance and bioavailability of the digoxin preparation used.

Assessment of antipyrine kinetics by measurement in saliva.

Abstract: The half-life of antipyrine has been estimated from saliva samples in ten subjects by a gas chromatographic method. Half-life, apparent volume of distribution and total body clearance estimated from saliva and plasma concentrations of antipyrine are not significantly different. The concentration of antipyrine in saliva is independent of flow rate within the range expected in healthy subjects in response to mechanical and sapid stimuli. Antipyrine estimation in saliva could facilitate many areas of phaamacokinetic research limited by the difficulty of obtaining serial plasma samples.

beta‐Adrenoceptor blocking activity and duration of action of pindolol and propranolol in healthy volunteers.

Abstract: The beta-adrenoceptor blocking activities of pindolol and propranolol have been investigated in healthy male volunteers. Pindolol was about forty times more potent than propranolol in reducing isoprenaline-induced tachycardia. Pindolol (5 mg) and propranolol (u99 mg) were approximately equiactive in reducing exercise-induced tachycardia, 2 h after oral administration. The duration of action of pindolol is significantly longer than that of propranolol; 24 h after pindolol (kmg), 36+/-5% of the masimum effect were still present, and after propranolol (100 mg) 16+/-4% remained. Despite the long duration of action of pindolol, there was no evidence for cumulation during oral administration of 5 mg t.d.s. for 5 days.

Treatment of phaeochromocytoma and of clonidine withdrawal hypertension with labetalol.

Abstract: 1 Labetalol has been used as medical treatment in five patients with phaeochromocytoma. 2 In four of the five patients, blood pressure was satisfactorily controlled, and symptoms and signs were relieved. 3 Labetalol also provided satisfactory cover across surgery for the removal of tumours in two cases. 4 In one instance, it was not possible to give sufficient labetalol orally to suppress the attacks of phaeochromocytoma. This patient was not effectively controlled at operation with a combination of propranolol and phenoxybenzamine. 5 Intravenous labetalol rapidly lowered blood pressure and relieved symptoms in a patient experienced hypertensive crisis after clonidine withdrawal. 6 Labetalol is a useful addition to the medical treatment of phaeochromocytoma.

Clinical pharmacokinetic studies of perphenazine.

Abstract: A gas-chromatographic method was used for the study in man of the kinetics of perphenazine (PPZ) and its sulphoxide metabolite (PPZ-SO). Various forms of PPZ administration were applied in eighteen schizophrenic patients and four healthy volunteers. Following an i.v. dose of 5 or 6 mg a considerable fluctuation in the plasma concentration was noted before the exponential elimination phase. The average terminal half-life of PPZ was approximately 9.5 hours. PPZ-SO showed up quickly but in low concentrations. After an oral dose of 6 mg no PPZ was detected in plasma and PPZ-SO only as traces. During continuous oral medication, 12 mg three times daily, a low systemic availability and a high PPZ-SO/PPZ ratio was found suggesting a marked first pass effect. PPZ-enanthate given i.m. fortnightly resulted in PPZ-levels comparable to those seen after continuous oral medication, but PPZ-SO concentration were much lower. No accumulation was observed. The systemic clearance rate (average approximately 100 1/h) was the same after PPZ-enanthate i.m. and PPZ i.v., but varied three-fold individually. Side effects were mostly, but not always, registered concomitant with high plasma levels of PPZ.

Biotransformation and excretion of lorazepam in patients with chronic renal failure

Abstract: To evaluate the effect of end-stage renal insufficiency and haemodialysis on the elimination of lorazepam, single oral doses of the drug (2.5 mg) were administered to normal subjects and patients with chronic renal failure (CC(r) : less than 2 ml/min) in the interdialysis period and during haemodialysis. The concentration of lorazepam and its major metabolite, lorazepam-glucuronide, were assayed using electron capture g.l.c. Plasma half-life (T1/2) of unchanged lorazepam in the patient group (11.3 +/- 0.6 h) was not different from that obtained in normals (11.1 +/- 0.9 h). Only minor quantities of the unchanged drug could be recovered in the 24 h urine in both groups: 0.3% of the ingested dose in normals and trace amounts in the patient group. No unchanged lorazepam could be detected in the ultrafiltrate from the coil kidney. Since the lower sensitivity of the method is about 5 ng/ml, this would indicate the in vivo binding of the active drug to plasma proteins to be at least 70%. The effect of haemodialysis on lorazepam plasma T1/2 was also insignificant (9.4 +/- 1.0 h). Urinary excretion of lorazepam-glucuronide was found to be considerably decreased in chronic renal failure associated with accumulation of high concentrations of this conjugate in plasma during days after a single oral dose. The plasma T1/2 of this conjugate in normals was 20.7 +/- 2.1 h. Roughly 35% of this main metabolite's concentration in plasma was detected in the ultrafiltrate from the coil kidney indicating the dialyzability of this conjugate and that the extent of plasma protein binding of lorazepam-glucuronide in vivo was approximately 65%. The above results indicate that after a single oral dose (2.5 mg) the biotransformation of lorazepam to its glucuronide conjugate remains unaltered and that high concentrations of this metabolite accumulate in plasma in the presence of severe renal function impairment.

Csf concentrations and serum protein binding of carbamazepine and carbamazepine-10, 11-epoxide in epileptic patients

Abstract: Serum and CSF samples of patients receiving chronic carbamazepine treatment were analysed. Daily fluctuations in serum levels of carbamazepine and carbamazepine-10,11-epoxide did not appear to be related to the dosage schedule, but some patients tended to have lower fluctuations when the carbamazepine was given more frequently. The epoxide/carbamazepine serum ratios varied greatly from patient to patient, and also fluctuated during the day for the same patient. Carbamazepine and carbamazepine-10,11-epoxide were present in CSF in concentrations ranging from 19 to 34% and 26 to 71% of the serum concentrations, respectively. There was a significant relationship between the free fraction of both drugs evaluated in vivo and the CSF/serum ratios. The need for a careful evaluation of the possible clinical effect of the epoxide is stressed.

The effect on blood pressure of beta-adrenoceptor blocking drugs administered once daily and their duration of action when therapy is ceased.

Abstract: The control of blood pressure achieved was similar whether pindolol or propranolol was given once or three times daily. When the drugs were ceased the antihypertensive effect lasted for longer than 24 h. There was no rebound hypertension. The full effect of the drug on blood pressure was seen within 24 h of its recommencement. Changes in blood pressure, pulse rate, and plasma renin activity occurred but these were not considered to be causally related. The response of plasma renin activity to posture was ablated when the patients were receiving beta-adrenoceptor blocking drugs.

The effects of low doses of amylobarbitone sodium and diazepam on human performance.

Abstract: The effects of diazepam (2.5 and 5 mg) and amylobarbitone sodium (50 and 100 mg) on performance and subjective effects were assessed in a group of twelve healthy subjects under standardised conditions. Treatments were administered orally at weekly intervals according to a balanced design and under double-blind conditions. The tests of performance most sensitive to drug effects in these healthy subjects were either prolonged and monotonous and gave the subject no feedback on performance, or required short term memory for efficient execution. Auditory vigilance was significantly impaired (P less than 0.05) between 45 min and 1 h 45 min after all drug treatments except amylobarbitone sodium (100 mg), compared with performance after lactose. At the same time false reports were significantly increased after amylobarbitone sodium (100 mg) compared with all other active drugs but not with lactose. These effects had disappeared 4-5 h post drug. Short term memory was impaired 1h 45 min after all treatments and impairment was dose related. No significant effects occurred 5h after treatment. Simple auditory reaction time was prolonged 2 h after the highest doses of amylobarbitone sodium and diazpam, and by amylobarbitone sodium (50 mg) 5 h 15 min after treatment. At this time the effects of diazepam had worn off. Digit symbol substitution was impaired by amylobarbitone sodium (50 and 100 mg), and diazepam (5 mg) after 2 h 45 minutes. No significant changes in visual search or tapping occurred after active drugs compared with lactose. Subjective ratings indicated both mental and motor impairment 2 h 45 min after all active preparations compared with scores after lactose though significant changes followed diazepam (2.5 mg) infrequently. Both correct detections and false reports in auditory vigilance tended to fall over the 6 separate days of testing, indicating an increase in caution. Visual search, short term memory, tapping and digit symbol substitution significantly improved with time, but there was no change in reaction time. From the limited information obtained by sampling blood at 3 and 6 h, no relationship between change in performance and plasma level was found in these subjects.

Methods for collecting individual components of mixed saliva: the relevance to clinical pharmacology.

Abstract: Methods are described for collecting constituents of mixed saliva, viz. parotid, submandibular, monor gland and sublingual saliva and gingival fluid. Literature is cited which showed that using these techniques, few antibiotics could be found in mixed saliva or its main components but all were detected in gingival fluid. Rifamicin and clindamycin were found in all components.

The effect of end-stage renal failure and haemodialysis on the elimination kinetics of sotalol.

Abstract: A single oral dose of sotalol (160 mg) was administered to control subjects with normal renal function and patients with chronic renal failure in the interdialysis period to estimate the elimination kinetics of the drug. Sotalol concentrations in body fluids were measured fluorimetrically using a modified Garrett and Schnelle (1971) method. Mean plasma half-life (T 1/2) was approximately 5 h in normals, 42 h in patients off-dialysis. During haemodialysis the mean plasma half-time was on the average 7 hours. Comulative urinary excretion of the drug was considerably lower in the patient group: 9% of the dose in 48 h as opposed to 61% in normals. Comparison of sotalol concentrations in plasma versus ultrafiltrate from the coil kidney indicates that the drug in vivo is negligible bound to plasma proteins in remal patients. The net-lowering effect of a 6 to 7 h haemodialysis on the plasma concentration decay line was by 20%. Post-dialysis plasma concentration data suggest that the rate at which sotalol returns to plasma from body tissues appears to be the rate-controlling factor in the elimination of sotalol by haemodialysis.

Comparison of propranolol and practolol in the management of hyperthyroidism

Abstract: Twenty-one hyperthyroid patients participated in an 8-week double-blind crossover trial of propranolol and practolol, and the effecte of these drugs on the clinical and metabolic features of the disease were studied. Propranolol was marginally more effective than practolol, as measured by the hyperthyroid diagnostic index and anxiety scale. Propranolol produced a significant reduction in the serum concentration ratio of tri-iodothyronine to thyroxine, compatible with partial inhibition of peripheral deiodination of thyroxine. Adverse reactions occurred more frequently with propranolol than with practolol. In veiw of the efficacy of practoloo, further trials in hyperthyroid patients of newer beta1-adrenoceptor antagonists, preferably without partial agonist activity, are indicated.

Labetalol in resistant hypertension.

Abstract: 1 The efficacy of labetalol in lowering blood pressure has been assessed in a group of 16 patients with severe hypertension whose blood pressure was inadequately controlled (supine diastolic blood pressure greater than 110 mmHg on two consecutive occasions) on existing therapy or in whom severe side-effects necessitated a change in therapy. 2 All patients had an original pretreatment supine diastolic blood pressure of greater than 120 mmHg and most had evidence of target organ damage. Patients were hospitalized for the purposes of changeover of therapy, labetalol being added to the existing regime which was reduced stepwise and eventually withdrawn. 3 Treatment with labetalol resulted in satisfactory blood pressure control in 10 of 16 patients in this study but high doses were required, the mean daily dose being 3,091 mg (range 1,200-8,000). 4 Treatment with discontinued in 6 patients on account of postural hypotension (3), failure to control supine diastolic blood pressure (2) and retention of urine (1). Long-term treatment was relatively free from side-effects. 5 From preliminary studies in animals it is suggested that an action within the central nervous system may contribute to the hypotensive effect of labetalol.

Haemodynamic long-term effects of a new beta-adrenoceptor blocking drug, atenolol (ICI 66082), in essential hypertension.

Abstract: 1 Thirteen men with untreated essential hypertension in WHO stage I were studied on an outpatient basis to evaluate the haemodynamic long-tern effect of a new beta-adrenoceptor blocker, atenolol. 2 Oxygen consumption, heart rate, cardiac output (Cardiogreen) and intraarterial branchial pressure were recorded at rest in a supine and sitting position and during steady state work at 300, 600 and 900 kpm/min. 3 The subjects were treated with atenolol (dose 100-200 mg/day) as the sole drug for 1 year and the haemodynamic study was repeated. 4 The blood pressure was reduced approximately 18% both at rest and during exercise, the heart rate approximately 25% and the cardiac output 16% at rest supine and 27% at rest sitting. During exercise the reductions in cardiac output were approximately 20%. The calculated total peripheral resistance was not decreased compared to pretreatment values. The mean arterial pressure-heart rate product was reduced almost 40%. 5 Apart from temporary muscular fatigue during the first weeks, no side-effects were seen. 6 Atenolol is an effective blood pressure lowering drug in mild and moderate hypertension, but the drop in blood pressure is associated with marked reduction in heart rate and cardiac output at rest as well as during exercise.

Haemodynamic effects of long-term oral labetalol.

Abstract: 1 The haemodynamic effects of labetalol have been studied in 11 hypertensive patients after 1 month of oral administration at a fixed dose of 800 mg/d. 2 Heart rate blood pressure and cardiac output were measured at rest and at two levels of exercise. 3 Labetalol significantly reduced heart rate and blood pressure at rest and after exercise but cardiac output remained unchanged. 4 The results suggest that labetalol is an effective anti-hypertensive agent acting by competitive adrenoreceptor blockade.

Altered distribution of digoxin in renal failure--a cause of digoxin toxicity?

Abstract: 1 Three cases are described in which renal failure was accompanied by a lowered apparent volume of distribution of digoxin. In two cases this resulted in frank digoxin toxicity and in one equivocal toxicity. In all three cases digoxin plasma levels were greater than 2 ng/ml. 2 The possible causes of the abnormal distribution of digoxin in renal failure are discussed. 3 Recommendations are outlined for the use of digoxin in patients with renal failure aimed at circumventing the problem raised by a lowered apparent volume of distribution of the drug.

Absorption of drugs by the lung

Abstract: 1 Ten patients undergoing diagnostic bronchoscopy had radioisotopically labelled drugs put directly into their bronchi; two received sodium cromoglycate, two salbutamol, three salmefamol and three rimiterol. 2 All four drugs were rapidly absorbed but higher peak plasma levels per unit dose were seen with sodium cromoglycate and salbutamol than with the other two drugs. 3 It is suggested that the lung metabolizes salmefamol and rimiterol but does not metabolize salbutamol or sodium cromoglycate.